22-28694086-C-T

Variant names:

• chr22-28694086-C-T
• rs17881378
• NM_007194.4:c.1407G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_007194.4(CHEK2):​c.1407G>A​(p.Val469Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,595,958 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V469del) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (1 hom.)
• Consequence: CHEK2 NM_007194.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 1.94
• Publications: 4 publications found

Genes affected

CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

CHEK2 Gene-Disease associations (from GenCC):

• CHEK2-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• Li-Fraumeni syndrome 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• acute myeloid leukemia

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 22-28694086-C-T is Benign according to our data. Variant chr22-28694086-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.94 with no splicing effect.
• BS2: High AC in GnomAd4 at 264 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007194.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	NM_007194.4	MANE Select	c.1407G>A	p.Val469Val	synonymous	Exon 13 of 15	NP_009125.1
	CHEK2	NM_001005735.3		c.1536G>A	p.Val512Val	synonymous	Exon 14 of 16	NP_001005735.1
	CHEK2	NM_001438293.1		c.1500G>A	p.Val500Val	synonymous	Exon 14 of 16	NP_001425222.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHEK2	ENST00000404276.6	TSL:1 MANE Select	c.1407G>A	p.Val469Val	synonymous	Exon 13 of 15	ENSP00000385747.1
	CHEK2	ENST00000382580.6	TSL:1	c.1536G>A	p.Val512Val	synonymous	Exon 14 of 16	ENSP00000372023.2
	CHEK2	ENST00000402731.6	TSL:1	c.1206G>A	p.Val402Val	synonymous	Exon 11 of 13	ENSP00000384835.2

Frequencies

GnomAD3 genomes AF: 0.00174 AC: 264 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000479 AC: 112 AN: 233786 AF XY: 0.000273

Gnomad AFR exome AF: 0.00699

Gnomad AMR exome AF: 0.000204

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000184

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000161 AC: 233 AN: 1443720 Hom.: 1 Cov.: 30 AF XY: 0.000134 AC XY: 96 AN XY: 718634

African (AFR) AF: 0.00575 AC: 192 AN: 33384

American (AMR) AF: 0.000201 AC: 9 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38012

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4130

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111476

Other (OTH) AF: 0.000416 AC: 25 AN: 60066

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74446

African (AFR) AF: 0.00604 AC: 251 AN: 41530

American (AMR) AF: 0.000589 AC: 9 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00218

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	4	Familial cancer of breast (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not specified (3)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	CHEK2-related cancer predisposition (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	8.5
DANN	Benign	0.73
PhyloP100		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17881378; hg19: chr22-29090074;